CLIMACTERIC 2015;18:108–109

Invited Editorial

The hope for KEEPS R. A. Lobo Department of Obstetrics & Gynecology, Columbia University, New York, New York, USA

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Key words: KEEPS, KRONOS EARLY ESTROGEN PREVENTION STUDY, MENOPAUSE

The Kronos Early Estrogen Prevention Study (KEEPS) provided a unique opportunity for a group of investigators to come together in an effort to determine the effects of different preparations of estrogen on coronary health in recently menopausal women, at a time when all clinical research in postmenopausal women had essentially stopped in the aftermath of the Women’s Health Initiative (WHI) study. We hoped to show a benefit of estrogen, compared to placebo, in intermediate markers of coronary atherosclerosis, as was suggested by other data such as the Estrogen in the Prevention of Atherosclerosis Trial (EPAT)1 and subgroup analyses from the WHI. In this regard, our findings were a disappointment2. It is likely that, because our participants were very healthy women, our study was underpowered to show any differences over the short duration of intervention. It was never the intent of KEEPS to assess risks associated with therapy, although we reported that there were no significant adverse events associated with treatment. KEEPS was designed to be an estrogen trial, because of the neutral effects observed with continuous combined estrogen  progestogen in the WHI. We have known about the potential attenuating effects of progestogens for more than 30 years3. Our intention was to use monthly vaginal progesterone for endometrial protection, in order to minimize the progestogenic attenuating effects. However, the FDA would not permit this strategy unless we were prepared to do annual endometrial biopsies for the length of the trial, which for us was unacceptable. In the aftermath of the WHI, even responsible professional societies were recommending the ‘lowest possible dose’ because of the potential of ‘early coronary harm’ and long-term cancer risks, which ultimately were proven not to be statistically significant events4. Accordingly, for KEEPS we chose the oral dose of 0.45 mg of conjugated equine estrogen (CEE), rather

than the standard dose of 0.625 mg CEE which had been studied extensively in the past. There has been difficulty in equating estrogenic potencies between types of estrogen and different routes of administration. This is because there are heterogeneous effects of different estrogens on different end-organs (liver, bone, brain, etc.)5. In the US, most clinicians equate 0.625 mg CEE to 1 mg micronized estradiol. However, this is not universally accepted, and in Europe 0.625 mg is considered to equate to 2 mg of estradiol, primarily because of the hepatic effects. Note that serum estrogen levels are not helpful here in that the potencies of the different B-ring estrogens in CEE are not measured, and we have shown that several B-ring estrogens have potent as well as modulatory effects on various endpoints6. My view has been that 0.625 mg CEE is closer to 1.5 mg of oral estradiol, looking at multiple endpoints. In trying to equate oral with transdermal estrogen, it is generally thought that micronized estradiol, 1 mg (achieving serum estradiol levels of 35–40 pg/ml and 200 pg/ml of estrone7) is roughly equivalent to transdermal estradiol 0.05 mg (achieving 50 pg/ml of estradiol and 50 pg/ml of estrone2), given a 3 : 1 relative potency of estradiol to estrone. Thus, we have considered that the dose of 0.45 mg CEE is as close as we can get, in practical terms, to equate with transdermal estradiol, 0.05 mg which are the doses we chose for KEEPS. We have 3 years of prospective data in KEEPS using two different estrogen preparations with different routes of administration on many different outcomes. While the beneficial effects of estrogen on various symptoms of menopause are well known, there are no prospective long-term data comparing oral and transdermal estrogen. We hope, and anticipate, that KEEPS will be able to provide important new information on various symptoms, as well as metabolic and other endpoints.

Correspondence: Professor R. A. Lobo, Department of Obstetrics & Gynecology, Columbia University, New York, New York, USA; E-mail: ral35@ columbia.edu INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1007428

The hope for KEEPS

Lobo

References extended post stopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353–68 5. Mashchak CA, Lobo RA, Dozono-Takano R, et  al. Comparison of pharmacodynamics properties of various estrogen formulations. Am J Obstet Gynecol 1982;144:511–18 6. Wilcox JG, Hwang J, Hodis HN, et  al. Cardioprotective effects of individual conjugated equine estrogens through their possible modulation of insulin resistance and oxidation of low density lipoprotein. Fertil Steril 1997;67:57–62 7. Lobo RA, Cassidenti DL. Pharmacokenetics of oral 17 beta-estradiol. J Reprod Med 1992;37:77–84

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1. Hodis HM, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis: a randomized, double blind, placebo-controlled trial. Ann Intern Med 2001;135:939–53 2. Harman SM, Black DM, Naftolin F, et  al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249–60 3. Lobo RA, Whitehead M. Too much of a good thing? Use of progestogens in the menopause: an international consensus statement. Fertil Steril 1989;51:225–31 4. Manson JE, Chlebowski RT, Stefanic ML, et  al. Menopausal hormone therapy and health outcomes during the intervention and

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